tbuckley/cabot-search huggingface dataset:
Single cell RNA sequencing to reveal immune microenvironment in primary and brain metastatic lesion of non-small cell lung cancer.
Authors: Feifei Teng, Menglin Bai, Chao Liu, Xiaohui Li, Xiangji Meng, Peiliang Wang, Jinming Yu
Journal: Journal of Clinical Oncology (2023)

e21009 Background: Despite immune checkpoint inhibitors (ICIs) have been proven effective in patients with advanced NSCLC, suboptimal therapeutic responses are seen in brain metastatic lesions. The heterogeneous cellular components in the tumor immune microenvironment (TIME) pose a challenge in understanding the low immune response. A comprehensive understanding of the heterogeneous TIME in primary and brain metastatic NSCLC is currently lacking, but crucial for improving ICI therapeutic responses in NSCLC patients with brain metastasis. Therefore, we use single cell RNA sequencing (scRNA-seq) to reveal distinct immune microenvironment in primary and brain metastatic lesion of NSCLC. Methods: Eight primary and nine brain metastatic NSCLC tumor samples were obtained through surgical resection. Immune cells (CD45+) were enriched through fluorescence-activated cell sorting (FACS) and subjected to scRNA-seq using the 10X Genomics platform. Sequencing reads were normalized and analyzed using R/Seurat package. Cellular components of each sample were determined based on known marker genes. Results: In our study, we observed a significant difference in the immune cell composition between primary and brain metastatic tumor samples. We found brain metastatic tumors are marked by an enrichment of TIMP1+ monocytes and PLTP+ tumor-associated macrophages (TAMs), both of which display heightened anti-inflammatory properties. In contrast, primary tumors exhibit an enrichment of FCN1+ monocytes and MARCO+ TAMs. Further analysis has revealed that the enrichment of TIMP1+ monocytes and PLTP+ TAMs is associated with a worse prognosis in patients receiving immunotherapy. Additionally, our examination of the transcriptome profile of CD8+ T cells showed an upregulation of inhibitory and exhausted signatures in brain metastatic tumor samples. Conclusions: Our study provided a comprehensive understanding of the TIME of primary and brain metastatic NSCLC and to gain deeper insights into the immunological mechanisms involved in the response to ICIs. The results of our study could prove valuable for the development of future immunotherapy strategies for NSCLC patients with brain metastasis.
Population pharmacokinetic-pharmacodynamic model of nirogacestat effects on B-cell maturation antigen in healthy subjects.
Authors: Todd Shearer, Rex L. Williams, Mark Johnson, Ewa Cendrowicz, Cathrine Leonowens, Margaret Smith, Todd Baughman, Caroline J. Breitbach, L. Mary Smith, Shinta Cheng
Journal: Journal of Clinical Oncology (2023)

8027 Background: B-cell maturation antigen (BCMA) is expressed on the membrane of normal plasma cells (PCs) and multiple myeloma (MM) cells and is the target of several investigational agents and approved products for MM treatment. Mechanistically, BCMA is cleaved from the cell surface by the enzyme gamma secretase, resulting in reduced levels of membrane-bound BCMA (mbBCMA) and release of soluble BCMA. Gamma secretase inhibitors (GSIs) have been shown to increase BCMA receptor density and potentiate the activity of several BCMA-targeted therapies in both clinical trials and in vitro studies. Although the effect of GSIs on BCMA receptor density has been well characterized in vitro, their effect on BCMA dynamics is incompletely understood in humans. This study sought to evaluate the pharmacodynamics (PD) of the GSI nirogacestat on mbBCMA in healthy subjects. Methods: A total of 23 healthy subjects were administered single doses of 50, 150, or 300 mg nirogacestat or multiple doses of 100 mg every 12 hours. Density of mbBCMA on PCs isolated from whole blood and bone marrow was measured by flow cytometry at baseline and 1, 2, 4, 8, 24, and 48 hours after single doses and 24 and 48 hours after the first dose in subjects receiving multiple doses. Nirogacestat serum concentrations were also measured at multiple time points to fully characterize the pharmacokinetics (PK). A population PK-PD model of the effect of nirogacestat on BCMA dynamics in humans was developed and used to simulate various administration dose levels and schedules to find an optimal nirogacestat regimen that continually increases mbBCMA over the dosing interval. Results: A 2-compartment model with linear absorption and elimination described serum nirogacestat in healthy subjects. A sequential PK-PD model that included an effect compartment and drug effect on mbBCMA cleavage rate described mbBCMA values. Simulations indicated that a 100-mg dose administered twice daily sufficiently maintained elevated and clinically relevant mbBCMA levels. Exposure and efficacy benchmarks from in vitro experiments and published clinical studies were used to contextualize simulations and hypothesize various dose and schedule scenarios to minimize dose of the BCMA-targeting therapy while maximizing BCMA potentiation. Conclusions: These results suggest that nirogacestat dose and schedule may have direct implications on the potentiation of BCMA-targeting therapies. Simulations suggest that the 100-mg, twice-daily nirogacestat dose results in elevated mbBCMA levels that could even allow for use of lower doses of BCMA-targeted agents while maintaining or improving efficacy. Study results along with this PK-PD model will be used to support nirogacestat dose and schedule in ongoing and planned studies in patients with MM.
Efficacy and safety of ripretinib in Chinese patients with advanced gastrointestinal stromal tumors (GIST) as ≥4th line therapy: Long-term update from a single-arm, phase 2 trial.
Authors: Jian Li, Xinhua Zhang, Yongjian Zhou, Jun Zhang, Ye Zhou, Ming Wang, Xin Wu, Yanhong Deng, Zhao Huang, Juan Dong, Lin Shen
Journal: Journal of Clinical Oncology (2023)

11543 Background: In INVICTUS study (NCT03353753), ripretinib as ≥4th line (4L) GIST therapy significantly improved median progression-free survival (mPFS) versus placebo (hazard ratio 0.15, 95% confidence interval [CI] 0.09–0.25; mPFS 6.3 vs 1.0 months) with a satisfactory safety profile. In the primary analysis (data cut-off: 26 Feb 2021) of the bridging study (NCT04282980) of INVICTUS, ripretinib as ≥4L therapy showed consistent efficacy and safety profiles in Chinese GIST patients to those in INVICTUS, with mPFS of 7.2 months and objective response rate (ORR) of 18.4% (7/38 patients). The overall survival (OS) data was immature at the primary analysis. Here we report the long-term updates of this bridging study. Methods: Patients received ripretinib 150 mg once daily continuously in 28-day cycles until progressive disease or other protocol-specified events for treatment discontinuation. The primary endpoint was progression-free survival (PFS) by independent radiologic review (IRR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 GIST-Specific Standard. Secondary endpoints included ORR by IRR, time to best response (TBR), duration of response (DOR), OS and safety. Adverse events were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Results: Overall, 39 patients were enrolled. Thirty-eight patients received continuous ripretinib treatment and were included in the efficacy analysis set. All 39 patients received at least one dose of ripretinib and were included in the safety set. The updated data cut-off was 23 Aug 2022. The overall median follow-up (90% CI) was 23.00 (11.99, 24.87) months. In the efficacy analysis set, mPFS (90% CI) by IRR was 6.44 (2.89, 8.31) months and ORR was 21.1% (8/38 patients). Median TBR and median DOR for the 8 patients with confirmed partial response were 2.25 and 8.57 months, respectively. The median OS (95% CI) in the efficacy analysis set was 25.56 (11.73, not evaluable) months. In the safety set, 20.5% of patients experienced ≥1 grade 3/4 treatment-related treatment-emergent adverse events (TRAEs). Compared to the primary analysis, the increase in TRAEs and new TRAEs leading to dose modification were minimal after 18 months of additional follow-up. Conclusions: After long-term follow-up, the more mature results continued to support the clinically meaningful benefit in PFS and also demonstrated clinically meaningful benefit in OS in Chinese ≥4L GIST patients, while the safety profile remained satisfactory. Clinical trial information: NCT04282980 .
The impact of cationic amphiphilic antihistamines on patients with lung cancer receiving immunotherapy.
Authors: Cho Hung Chiang, Cho Han Chiang, Xin Ya See, YUANPING HSIA, Chun-Yu Peng, Chuan-Sheng Horng, Yu-Cheng Chang, Shih-Syuan Wang, Cho Hsien Chiang, Cheng-Ming Peng, Her-Shyong Shiah
Journal: Journal of Clinical Oncology (2023)

e21078 Background: H1-antihistamines are long-used medications for the treatment of allergies. In preclinical studies, antihistamines, particularly those with cationic amphiphilic properties, have been found to have anti-tumor effects. In observational studies, H1-antihistamines have been associated with improved survival in patients receiving immune checkpoint inhibitors (ICIs) in pan-cancer association studies. However, the impact of antihistamines on lung cancer is unclear. We aim to evaluate the effect of antihistamines on lung cancer patients receiving ICIs. Methods: We conducted a retrospective cohort study at two tertiary referral centers in Taiwan involving lung cancer patients receiving ICI therapy. Antihistamines were subclassified into cationic amphiphilic and non-cationic amphiphilic antihistamines according to their lipophilic properties. The primary endpoint was overall survival (OS) and the secondary endpoint was progression-free survival (PFS). Results: We identified 336 lung cancer patients receiving ICIs, of which 294 were antihistamine users (43 cationic amphiphilic and 222 non-cationic amphiphilic) and 42 were non-antihistamine users. Compared with non-antihistamine users, antihistamine users had a longer OS (median 24.4 vs. 6.4 months, p = 0.002) and PFS (median 8.2 versus 4.1 months, p = 0.049). Among antihistamine users, cationic amphiphilic antihistamine users had a longer OS (median 38.0 versus 17.8 months, p = 0.015) and PFS (median 17.5 versus 6.2 months, p &lt; 0.001) than non-cationic amphiphilic antihistamine users. In Cox proportional hazard analysis, antihistamines and particularly cationic amphiphilic antihistamines were associated with a 30-55% lower risk of all-cause mortality and disease progression. Conclusions: The use of antihistamines, particularly those with cationic amphiphilic properties, was associated with improved outcomes among lung cancer patients undergoing immunotherapy.[Table: see text]
Patients harboring uncommon EGFR exon 19delins variants of advanced non-small-cell lung cancer and response to osimertinib: A multi-center retrospective study.
Authors: Zhiqin Lu, Yali Yi, Yuxi Luo, Zhimin Zeng, Hui Luo, Yun Shu, Anwen Liu
Journal: Journal of Clinical Oncology (2023)

e21184 Background: This study aims to investigate the efficacy of different EGFR inhibitors therapy in patients with advanced non-small-cell lung cancer (NSCLC) harboring atypical EGFR exon 19delins variants. Methods: Targeted sequencing database of 1426 treatment-naive patients with advanced NSCLC were retrospectively screened for EGFR exon 19 deletion (19del) variants in a multi-center study from January 2017 to January 2022, and 34 patients with uncommon EGFR exon 19 deletion-insertions (19delins) were included. The response rate, and progression-free survival (PFS) were analyzed according to the radiographic images. Results: We identified 3 previously unreported uncommon EGFR exon 19delins variants. Among the 34 patients who had uncommon EGFR19delins, 24 patients received first-generation, and 10 patients received third-generation as front-line EGFR TKI therapy, the median progression-free survival (mPFS) was significantly longer for patients who received first-generation than those with third-generation (19.1 months vs 6.9 months; HR: 0.18, 95% CI: 0.062-0.507; p &lt; 0.001). At progression, EGFR T790M was the main acquired mechanism of resistance (8/14; 57.2%). There were 22 patients who received osimertinib therapy, the overall ORR and DCR were 54.5% and 81.8%, respectively, and the overall mPFS was 6.9 months. But no significant difference was observed in mPFS between first-line osimertinib and second-line osimertinib therapy (6.9 months vs. 3.8 months; p = 0.206). Conclusions: The uncommon EGFR exon 19delins variants of advanced NSCLC have longer mPFS for the first-generation compared with the third-generation as front-line EGFR TKI therapy, and respond poor to third-generation EGFR inhibitors, regardless of whether osimertinib was used as first-line or second-line therapy. Patients with uncommon EGFR exon 19delins may be a biomarker of poor efficacy with the third-generation EGFR TKI therapy.
Optimal number of lymph node stations associated with improved survival among patients with non-small cell lung cancer (NSCLC).
Authors: Meredith Ray, Anberitha T Matthews, Olawale Akinbobola, Matthew Smeltzer, Carrie Fehnel, Nicholas R Faris, Andrea Saulsberry, Kourtney Dortch, Samuel Muhit, Raymond U. Osarogiagbon
Journal: Journal of Clinical Oncology (2023)

8571 Background: Good quality pathologic nodal evaluation is associated with improved long-term survival in NSCLC after surgical resection. However, there is no universal definition of quality. We examined the association between number of lymph node stations (NLNS) sampled and overall survival. Methods: We examined the population-based Mid-South Quality of Surgical Resection (MS-QSR) cohort, excluding patients with neoadjuvant therapy, positive margins, and secondary resections. We summarized demographic and clinical characteristics with appropriate statistics. We employed four Cox regression models: 1) including NLNS as the only predictor; 2) model 1, adjusting for age, sex, histology, clinical stage, extent of resection, and surgical technique; 3) examined the impact of pathologic staging (pStage in 3 groups: IA/IB[&lt;4cm tumor size]; IB[&gt;4cm]/II/IIIA[pN2-]; pN2]) by modeling interaction with pStage and NLNS; 4) model 3 plus adjustments (no clinical stage). In a cut point analysis to identify the optimal NLNS for improved survival, we dichotomized the NLNS for cut points 0 to 12. Hazard ratios (HR) were calculated (as above) and plotted for each dichotomization. Results: The 3916 eligible patients were 21% Black, 54% male, 15% on Medicaid and 49% Medicare; 84% and 85% had clinical and pathologic stage I/II, respectively; 84% had no invasive staging; 84% had a PET-CT scan. For every additional lymph node station sampled, the HR decreased by 0.94 (95% confidence interval: 0.92, 0.96). After adjustments, the HR remained significant (Table). Our pStage cohorts comprised of 2474 (64%) IA/IB[&lt;4cm]; 1080 (28%) IB[&gt;4cm]/II/IIIA[pN2-]; and 290 (8%) pN2+. Once stratified, HRs remained significant among those with early stage but not for pN2+ (Table). When further adjusted, only pStage IA/IB[&lt;4cm] patients had a significant HR, 0.94 (0.91, 0.97). The cut point analysis indicated sequential survival improvement up to ≥ 7 total stations sampled, consistently across all models/adjustments. Conclusions: The number of lymph node stations examined is directly associated with survival after lung cancer resection. Examination of a total of 7 intrapulmonary, hilar and mediastinal stations seems optimal. Hazard ratios (95% confidence intervals) for modeling hazards as a function of lymph node stations sampled (model 1), further adjusted for age, sex, histology, clinical stage, extent of resection, and surgical technique (model 2), including interaction with pathologic stage with no adjustments (model 3), and interaction with pathological stage with adjustments (no clinical stage) (model 4). [Table: see text]
Addressing resiliency and burnout: A quantitative needs assessment of oncology physician assistants (PAs).
Authors: Eric Daniel Tetzlaff, Heather Marie Hylton, Karen J Ruth, Zachary Hasse, Michael J. Hall
Journal: Journal of Clinical Oncology (2023)

11016 Background: Significant progress has been made in understanding the factors associated with oncology (onc) PA burnout. However, little is known about what PAs need to mitigate burnout, the availability of resources, and barriers to interventions. Methods: A national survey of onc PAs was conducted in 2022. PAs completed a quantitative needs assessment to determine the importance of and their perceived skills in topics of self-care, clinical care, and professional development. For importance, “high importance” included ratings of ‘Essential’ or ‘Very Important’; for perceived skill, “high skill” included ratings of ‘Excellent’ or ‘Good’. Engagement with employee assistance programs (EAPs) was examined. Resiliency &amp; Burnout were assessed using the Connor-Davidson Resilience Scale &amp; the Maslach Burnout Inventory. Results: PAs (n = 171) were mostly practicing in medical oncology (66%) and outpatient (66%). The high importance topics most often identified were dealing with difficult patients (93%), dealing with difficult providers (89%), delivering bad news (88%) and coping with death / patient suffering and personal grief (86%). Topics less often reported as high importance included opportunities to be a mentor (61%), professional coaching (59%) and mindfulness skills (53%). PAs frequently reported high skills in dealing with difficult patients (75%), delivering bad news (72%), and resiliency skills (59%). Fewer PAs reported high skills for debriefing following significant events (49%) and mindfulness skills (42%). Burnout (BO) rates were higher for those with lower perceived skills in resiliency (p = 0.03) and dealing with difficult providers and staff (p = 0.03) but did not differ based on importance of any topics. Resiliency significantly increased with increasing levels of reported importance for the mindfulness skills training, cognitive skills training, and debriefing after significant events topics. Resiliency significantly increased with increased levels of perceived skill for all topics explored. Common barriers to well-being EAP participation were lack of time (58%) and concerns about confidentiality and stigma (26%). For PAs with concerns about stigma, resiliency scores were lower (6.4 vs 7.0; p &lt; 0.001) and BO rates were higher (73% vs 47%; p = 0.005). Conclusions: Perceived deficiencies in resiliency training and managing difficult work relationships correlate with higher rates of burnout in onc PAs. Barriers to participation in EAPs, which may help address these deficits, are common and when present are associated with an alarming rate of burnout and lower resiliency. Cultural change in medicine is needed to reduce perceived and experienced stigmatizing experiences to address burnout. These findings suggest that burnout interventions which focus on building resiliency and managing work relationships are crucial and may be best implemented outside of the workplace.
Healthcare resource use for pediatric low-grade glioma care: A cohort of linked electronic health records and claims data.
Authors: Tab Cooney, Sandie Yu, Shailaja Daral, Michelle Field, Blake Krebs, Mark Kieran, Peter Manley, Sandya Govinda Raju, Susan Zelt
Journal: Journal of Clinical Oncology (2023)

10038 Background: Pediatric low-grade glioma (pLGG) is the most common brain tumor in children and is associated with persistent long-term tumor- and treatment-related morbidities. This study aims to characterize the costs associated with the treatment of pLGG. Methods: A retrospective study using the Optum de-identified Market Clarity Dataset linked claims (commercial, Medicare Advantage and Managed Medicaid beneficiaries) and electronic health records (EHRs) of cases ≤18 years of age, with an ICD-10 code for brain neoplasm and ≥1 physician notes between January 2017 and June 2018 was performed. Index date was the first claim or EHR with an ICD-10 code for brain neoplasm. Natural language processing was used to identify pLGG-relevant data from physician notes. The observation period included 3 months prior to index date and 6-month segments from index date for 36 months. Cases had either continuous insurance coverage or continuous EHR activity during this period. Results for procedures and medication use were reported as averages throughout the 36-month post-index follow-up period. Results: A total of 154 patients with pLGG were identified. Median age was 11 years (range 2–18). Among the cohort, 49% (n=76) were female; 75% (n=116) were non-Hispanic white, 13% (n=20) Hispanic, 5% (n=7) African American, 1% (n=1) Asian and 6% (n=10) other/unknown. Of benefits, 56% had commercial and 44% Medicaid. Brain imaging and neuropsychological evaluations were performed at least once in 85% and 57% of the cohort, respectively. Among pLGG relevant medications, 57% of the cohort used analgesics, 45% anti-emetics, 32% anxiolytics, and 29% anticonvulsants. A total of 100 patients received ≥1 pLGG disease control treatments: Of these, 53% underwent emergency brain surgery, 24% had planned brain surgery, 14% received chemotherapy, and 6% received targeted therapy. Of the 100 patients who received disease control treatments, 57% relapsed after first-line treatment; 37% of patients received 2 lines of therapy, and 20% of patients received ≥3 lines of therapy. Conclusions: Our findings show that patients with pLGG often require long-term medical care and high levels of healthcare resources to treat their disease and its sequalae. Additionally, a majority will relapse and face a higher burden of disease. Further studies using integrated data sources are warranted to help us understand the burden of pLGG and inform evidence-based health care planning for these patients.